NEURAL AND ENDOCRINE CONSEQUENCES OF PARITY

大多数成年雌性哺乳动物繁殖活跃，生育一次或多次。然而，令人惊讶的是，很少有人注意到先前的生殖经验对成年女性内分泌和神经功能可能产生的长期影响。目前的建议是基于这样的发现，即胎次会导致女性循环催乳素（PRL）和雄激素的长期改变，在经历过生育的大鼠中，PRL分泌也会减少，而在女性和大鼠中，多巴胺能张力都会增加。这一建议的总体目的是表征的程度和基础的内分泌和神经变化引起的前胎。第一个系列的研究将描述胎次对已产和未产雌性大鼠垂体RL和雌二醇分泌的影响。胎次对雌激素受体的影响，以及胎次是否会降低雌激素对PRL的反馈调节。接下来，将测量泌乳期间PRL升高对成年后自身分泌的贡献。第二个系列的实验将确定产羔如何增加多巴胺能功能，这种增加可能是产羔动物PRL分泌减少的基础。将测量胎次对多巴胺受体的影响，介导多巴胺作用的第二信使，以及下丘脑和下丘脑外区域多巴胺释放的雌激素调节（使用体内微透析系统结合HPLC）。多巴胺神经元对PRL调节的敏感性可能会降低，因为先前的胎次将被评估。第三组研究将检查胎次对PRL分泌的影响是否与年龄有关。初产年龄对成年后期循环雌激素水平的影响以及雌激素对PRL分泌的调节作用将被确定。总的来说，这些研究将确定导致前一次胎次产生的成年雌性内分泌和神经功能改变的潜在机制，这些改变可能影响雌性一生中广泛的生物过程，包括行为、生殖能力、免疫功能和激素分泌。

Most adult female mammals are reproductively active and give birth once or multiple times. Surprisingly, little attention, however, has been given to the possible long-term effects of prior reproductive experience on endocrine and neural functions in adult females. The present proposal draws upon the finding that parity produces long-term alterations in circulating prolactin (PRL) and androgens in women, similar reductions in PRL secretion in reproductively experienced rats, and an increase in dopaminergic tone in both women and rats. The overall aim of this proposal is to characterize the extent and basis of the endocrine and neural changes induced by prior parity. The first series of studies will characterize the effects of parity on pituitary RL and estradiol secretion in parous and nulliparous female rats. The effects of parity on estrogen receptors and whether parity produces a reduction in estrogen feedback regulation on PRL will then be investigated. Next, the contribution of elevated PRL during lactation on its own secretion later in adulthood will be measured. The second series of experiments will determine how parity may increase dopaminergic function, an increase which may underlie the reductions in PRL secretion in parous animals. The effects of parity on dopamine receptors, second messengers that mediate dopamine action, and estrogenic regulation of dopamine release both in hypothalamic and extrahypothalamic areas (using an in vivo microdialysis system combined with HPLC) will be measured. The possible decrease in sensitivity of dopamine neurons to PRL regulation as a result of prior parity will then be evaluated. The third set of studies will examine whether the effects of parity on PRL secretion are age-dependent. The effects of the age of first parity on circulating estrogen levels late in adulthood and estrogen regulation of PRL secretion will be determined. Overall, these studies will identify underlying mechanisms which contribute to the alterations in endocrine and neural functions produced by a previous parity in the adult female, alterations which may affect a wide spectrum of biological processes, including behavior, reproductive fertility, immune function, and hormone secretion, over the life span of the female.